The objective of this project is to develop new estriol formulation(s) that are effective as hormone replacement therapy-protecting the coronary arteries against hyperreactivity and relieving cardiovascular menopausal symptoms of ovarian steroid deficiency. Such coronary hyperreactivity results at least in part from the deficiency of estrogens after the cessation of ovarian function. This project will also further develop the primate cellular model of cardiovascular risk due to loss of ovarian function in post-menopausal women. The anticipated new commercial product will be a formulation designed to replace the estrogenic component with a natural estrogen metabolite that is normally found in high concentrations during pregnancy, but less intensely stimulates estrogen receptors. Estriol does not appear to increase the risk of breast or uterine carcinoma; instead, it is reported to decrease the risk of cancer. The estriol skin cream is designed to provide protection against cardiovascular events as a pleasant, cosmetic- like formulation that can achieve improved compliance among those who initiate hormone replacement therapies. Because protection for the cardiovascular system provided by estrogens can be expected to persist for only 2-4 weeks after estriol treatment ends, estriol should be offered in a form attractive for long-term compliance. Skin cream formulations are well accepted by women, and provide skin storage and slow release that are suitable for a daily treatments that we hypothesize may reduce the probability of cardiovascular events. Although the risk of death due to cardiovascular causes is nearly 50% for post-menopausal women, and is far greater than any other risk, presently available forms of hormone replacement therapy are neither well understood nor readily accepted. Estriol skin cream will offer a pleasant form of protection and improved quality of life. PROPOSED COMMERCIAL APPLICATIONS: The commercial application will be a percutaneous formulation of estriol in a formulation that will produce blood levels sufficient to minimize the risk of cardiovascular disease. The product is expected to find widespread application in hormone replacement therapy, resulting in improved acceptance among post-menopausal women, and thus a large and growing market.